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Citing Possible Heart Risks, FDA Recommends Increased Monitoring, Tighter Indications, for MS Patients Prescribed Fingolimod

Hurley, Dan

doi: 10.1097/01.NT.0000415800.41952.c3
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Following the death of a patient taking fingolimod, the FDA issued new guidelines for cardiac monitoring of multiple sclerosis (MS) patients receiving the drug, and has advised against its use altogether in those with certain pre-existing or recent heart conditions or stroke.

Increasingly concerned about the potential risks of heart-rate slowing following the first dose of fingolimod (Gilenya), the FDA has issued new recommendations for cardiac monitoring of multiple sclerosis (MS) patients receiving the drug, and has advised against its use altogether in those with certain pre-existing or recent heart conditions or stroke.

The recommendations, issued on May 14 following an extensive review prompted by the death of a patient within 24 hours of initial dosing, include hourly pulse and blood pressure measurement for at least the first six hours following initiation of fingolimod, and electrocardiogram testing prior to dosing and at the end of the observation period. Longer observation, including the use of overnight cardiac monitoring, is recommended for patients who are at higher risk for bradycardia

The new monitoring requirements will likely exceed the in-office capabilities of many neurologists, prompting them to coordinate with cardiologists or specialized clinical care centers, MS specialists told Neurology Today.

“Most neurologists' offices are not set up to do cardiograms and to have them read quickly,” said Jeffrey A. Cohen, MD, a professor of neurology at the Cleveland Clinic Mellen Center for Multiple Sclerosis who has authored several studies on the risks and benefits of fingolimod. “Everybody's going to have to figure out how they're going to do the monitoring, either by sending the data via telemetry to a cardiologist in their center or by admitting patients to a unit that has monitoring capacity.”

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The co-author of a recent paper in the New England Journal of Medicine reviewing the use of fingolimod for MS said he sees the new recommendations for increased monitoring as part of a broader trend for immunotherapies targeting the disease.

“I believe that as we move to more specialized forms of immunotherapy with various side effects, patients should be treated at MS centers which have the expertise to do that,” said David A. Hafler, MD, chairman and professor of neurology, and professor of immunobiology, at the Yale School of Medicine.

“It's not just the monitoring for cardiac toxicity of this drug,” Dr. Hafler added, “but for all the toxicities associated with different types of immunotherapies. If it were done in a neurologist's private office, it would obviously present a problem. At Yale we have an interventional neurology unit, and we treat patients at an infusion center. As the therapies get more complex, it requires the expertise associated with infusion centers and doctors who know how to monitor.”



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The FDA's review of the drug, approved in September of 2010, began after the death of an MS patient 23 hours after her first dose of fingolimod, even though no apparent abnormalities had been observed by her physician in the first six hours following initiation of therapy. The patient, who died in November 2011, had been taking two blood-pressure medications, metoprolol and amlodipine, both of which can affect heart rate. The patient was also found to have extensive brainstem MS lesions, which are associated with sudden death.

A link between the first dose of fingolimod and the death could neither be ruled out nor definitely proved, the FDA concluded. But it decided to re-evaluate clinical trial data related to the effects of fingolimod on heart rate and blood pressure, including data from trials that had not been completed when the drug was approved.

Examining the drug's effect on heart rate by 24-hour cardiac monitoring, it found that the rate-lowering effect of fingolimod has two phases, “with an initial decrease within 6 hours, and a second decrease, in part related to a circadian rhythm, around 12 to 20 hours post-dose,” the agency stated in a safety announcement released on May 14.

The FDA recommended that monitoring be continued past six hours in patients who experience a heart rate of less than 45 beats per minute in the first six hours, or in those who had their lowest heart rate at six hours post-dose, as further bradycardia is still possible after six hours. Extended monitoring is also now recommended in patients with certain pre-existing conditions, such as QT prolongation, and in patients receiving concurrent drugs that slow the heart rate or atrioventricular conduction, such as beta-blockers.

Julie Masow, a spokesperson for Novartis, which manufactures the drug, stated in an e-mail that the FDA's new recommendations are “a validation of the updated prescribing information for Gilenya that Novartis announced on April 20. Novartis believes that Gilenya [fingolimod] represents an important treatment option for many patients with relapsing MS and that the benefit/risk profile of fingolimod remains favorable for appropriate patients when used according to the updated label.”

With nearly 800 patients treated with fingolimod at the Cleveland Clinic Mellen Center for Multiple Sclerosis, “We've had no symptomatic or significant cardiac problems,” Dr. Cohen said. But, he said, the center already followed many of the FDA's new recommendations. “We've always taken a cardiogram beforehand. If there's any abnormality, even a minor one, we typically get a cardiologist's input. And we usually exclude patients on beta-blockers.

“I think the stricter guidelines in terms of eligibility as to who's an appropriate patient are much more useful than the additional required cardiograms before and after,” he added. “The more explicit recommendations for who should be kept longer and who should be monitored overnight also are useful.”

John Corboy, MD, professor of neurology at the University of Colorado in Aurora and director of the clinical program at its Multiple Sclerosis Center, said: “It will be a little complicated for patients who have documented vascular disease and are using various medications where they might need more significant monitoring. The argument could be made that a lot of those patients shouldn't even be treated with fingolimod.” [Dr. Corboy serves on the Neurology Today editorial advisory board.]



Even after reviewing all known deaths in patients taking fingolimod, the FDA concluded that the number of deaths of apparent cardiovascular origin or of unknown origin among MS patients taking fingolimod “does not appear to be higher than in MS patients not treated with Gilenya.”

Dr. Corboy, who has consulted with Novartis as a member of its medical advisory board for the drug, said: “There are very little data from either Holter monitoring or EKGs that there's any cardiac risk associated with the drug. Patients have to weigh that against the known risks of MS.”

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• A copy of the FDA's May 14 safety announcement can be found online :
    • Pelletier D, Hafler DA. Fingolimod for multiple sclerosis. N Engl J Med 2012;366:339–347.
      ©2012 American Academy of Neurology